(a) Field of the Invention
This invention relates to novel substituted 2-(3-aminophenoxymethyl)imidazolines of Formula I principally useful in the treatment of diarrhea and also useful as analgesics.
Diarrhea is a condition characterized by an abnormally frequent discharge of liquid or semi-liquid from the bowel. The normal intestinal discharge occurs at variable intervals but usually not more than twice in twenty-four hours and typically has a semi-solid consistency. When a more liquid stool must be discharged more than three times a day, diarrhea exists. Diarrhea may have any of several causes. For example, eating indigestible or irritating foods or foods to which an individual is allergic may cause diarrhea. Too much roughage, such as found in bran, cabbage, or other fibrous foods often consumed to relieve constipation, may also induce diarrhea. Infection or nervousness, which can cause discharge before the intestinal contents can assume a normal form, are causes of diarrhea. Moreover, many drugs, particularly antibiotics, are known to cause diarrhea as a side effect.
Mild diarrhea has been treated with binding agents such as aluminum hydroxide gel, kaolin, pectin, and bismuth. More serious diarrhea has been treated with opiates, which act through a spasmogenic effect that inhibits propulsive activity in the intestine. Diphenoxylate (a synthetic opiate derivative), tincture of opium, and camphorated tincture of opium (paregoric) have all been used effectively for serious diarrhea. The compounds, however, treat symptoms rather than causes and have all the problems associated with opiates, such as addictive liability, mental confusion or discomfort, respiratory depression, nausea, and the like. Thus, care must be taken to avoid complications and even death.
Analgesics are agents used in the treatment of pain and often are useful in alleviating inflammation. The major classes of analgesics include narcotic analgesics (or opiates) and analgesic-antipyretics such as the salicylates. Although the efficacy of opiates in relieving pain is well-established, the associated addiction liability is a distinct disadvantage. Although salicylate and salicylate-like agents are also efficacious in relieving pain, they often exhibit undesirable side effects such as gastrointestinal irritation (as with aspirin) or liver toxicity with extended use (as with acetaminophen). The compounds included in this invention are neither opiates nor salicylates and may be expected not to exhibit the disadvantages of either class of compound.
(b) Prior Art
Certain substituted 2-(phenoxymethyl)imidazolines are known--U.S. Pat. Nos. 3,966,757 and 4,025,639 (both to A. Nattermann & Cie. GmbH.), and South African patent application Nos. 76/1508 (Takeda Chemical Industries Ltd.) and 78/2449 (Ciba-Geigy A.G.)--but differ significantly from the present compounds. In the previously disclosed compounds, the phenyl nucleus bears only hydrogen, alkyl, alkoxy, nitro, or halogen substituents, but never bears amino or substituted-amino groups as disclosed here for the first time. Moreover, the prior art compounds were disclosed as hypotensives U.S. Pat. Nos. 3,966,757 and 4,025,639 and as parasiticides (76/1508 and 78/2449).